Discussion
Here we present a complicated case of reactivation TB in a patient being treated for warm autoimmune hemolysis complicating anemia of chronic disease and RA/SLE overlap syndrome. As far as we know, this is the first case of reactivation TB complicated by RA/SLE overlap syndrome. The acuity and severity of her hemolytic anemia necessitated high-dose pulse-steroid therapy, with the unfortunate result of facilitating TB reactivation. IGRA assays performed while the patient was on immunosuppressive therapy were negative, and possible reactivation TB was not considered until high-dose corticosteroid therapy began.
Pulmonary and extrapulmonary TB are common complications in the treatment of autoimmune diseases.3 While relatively rare in the United States (incidence of 2.7 cases per 100,000 persons in 2019)4, TB is one of the most common global etiologies of infectious disease, infecting approximately 1.7 billion people as of 2018 (~23% of the global population)5. Of those exposed, patients being treated for autoimmune conditions such as SLE or RA are particularly susceptible to active infection. Decreased production and secretion of interferon-gamma (IFN-γ) related to therapy with corticosteroids or TNF-a inhibitors (i.e., adalimumab) weakens phagocytotic response, facilitating TB re-activation1,6,7. Further, the high-dose immunosuppression blockades IFN-γ release by Th1 cells, reducing detection of latent TB infection (LTBI) by IGRA1,6,7.
In the acute treatment of uncontrolled rheumatological conditions, high doses of corticosteroids or other immunosuppressants are often first-line agents8. However, in patients with latent TB infection, immunosuppression may only be appropriate where infection precautions are in place. In cases with unknown TB status, a cautious approach may be preferred, although guidelines for this specific clinical circumstance are lacking. In our case, high-dose corticosteroid therapy for AIHA likely facilitated TB activation, leading to the development of necrotizing pneumonia and potentially exposing the healthcare staff. Fortunately, there have been no healthcare-associated TB infections to date, likely due to the absence of productive cough in the patient and the increased infection control interventions in place during the coronavirus pandemic.
Detection and treatment LTBI in immunocompromised patients is complicated and often controversial9. Currently, there are no clear universally accepted guidelines for TB detection and screening in those being treated for autoimmune conditions with corticosteroids. However, guidelines for LTBI in other immunocompromised populations, such as those with solid organ transplants, may be useful. These suggestions my vary but often recommend a two-stage screening approach using a Tuberculin skin test (TST, positive ≥5 mm) and IGRA10,11. However, in patients receiving inhibitors of TNF-a and related pathways, these tests are insufficient to rule out latent infection as TNF-a inhibitors significantly reduce these tests’ negative predictive value12.
Some studies suggest chest x-ray (CXR) may be useful as a screening tool where immunoassays are unreliable, however its utility in diagnosing latent infection is controversial13. Further chest CT (CCT) may also be useful following CXR situations, with the imaging modality detecting 89% of those with latent TB13,14. In general, IGRA should not be used alone as a screening or diagnostic tool in patients with suppressed Th1-immune responses and should be interpreted with caution given their propensity for false-negative results in these settings9. While none of these tests are 100% sensitive, combining TST, IGRA, CXR and CT may be indicated when attempting to rule out latent infection.
For high-risk immunocompromised individuals we recommend screening with, IGRA, TST and CXR to increase sensitivity. If CXR is inconclusive or there is high clinical suspicion of LTBI consider additional chest CT imaging. If CXR or CT come back with signs of latent TB infection (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening), it is important to get a clear patient history to evaluate other granulomatous disease including histoplasma and sarcoidosis.
Consider treating patients using national guidelines15, if IGRA or TST is positive (TST, positive ≥5 mm) or if the patient has a history of untreated LTBI. In patients with negative IGRA/TST and positive imaging, consider treating those with high clinical suspicion of latent infection, including previous incarceration, known exposure, or time spent in TB endemic regions. Finally, consider treating anyone undergoing immunosuppressive therapy who has had prolonged contact with an individual with active TB regardless of immunoassay or imaging results.11
In patients with high clinical suspicion for LTBI with respiratory or systemic syndromes, preferred diagnostic strategies include lung imaging, sputum stains, MTB-PCR, and mycobacterial cultures as they are unaffected by systemic immunosuppression. Of these, MTB-PCR is likely the best choice, as highly specific results can be obtained within a matter of hours16. However, this test is only useful in ruling out active disease and should not be used to rule out LTBI. Finally, isolation precautions should be considered in patients undergoing immunosuppressive therapy with high clinical suspicion of LTBI despite negative IRGA.